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Taming lupus—a new understanding of pathogenesis is leading to clinical advances

Nature Medicine volume 18, pages 871–882 (2012)Cite this article

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Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease that is characterized by the loss of tolerance to nuclear self antigens, the production of pathogenic autoantibodies and damage to multiple organ systems. Over the years, patients with SLE have been managed largely with empiric immunosuppressive therapies, which are associated with substantial toxicities and do not always provide adequate control of the disease. The development of targeted therapies that specifically address disease pathogenesis or progression has lagged, largely because of the complex and heterogeneous nature of the disease, as well as difficulties in designing uniform outcome measures for clinical trials. Recent advances that could improve the treatment of SLE include the identification of genetic variations that influence the risk of developing the disease, an enhanced understanding of innate and adaptive immune activation and regulation of tolerance, dissection of immune cell activation and inflammatory pathways and elucidation of mechanisms and markers of tissue damage. These discoveries, together with improvements in clinical trial design, form a platform from which to launch the development of a new generation of lupus therapies.

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Figure 1: The spiral of disease progression in SLE.
Figure 2: The role of SLE risk alleles in the pathogenesis of SLE.
Figure 3: Recognition of nucleic acids by innate immune cells triggers cytokine production.
Figure 4: Mechanisms for organ damage.

References

  1. Lateef, A. & Petri, M. Biologics in the treatment of systemic lupus erythematosus. Curr. Opin. Rheumatol. 22, 504–509 (2010).

    PubMed  Google Scholar 

  2. Navarra, S.V. et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet 377, 721–731 (2011).

    CAS  PubMed  Google Scholar 

  3. Furie, R. et al. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum. 63, 3918–3930 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Morel, L. et al. Genetic reconstitution of systemic lupus erythematosus immunopathology with polycongenic murine strains. Proc. Natl. Acad. Sci. USA 97, 6670–6675 (2000).

    CAS  PubMed  Google Scholar 

  5. Lauwerys, B.R. & Wakeland, E.K. Genetics of lupus nephritis. Lupus 14, 2–12 (2005).

    CAS  PubMed  Google Scholar 

  6. Harley, J.B. et al. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat. Genet. 40, 204–210 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Deng, Y. & Tsao, B.P. Genetic susceptibility to systemic lupus erythematosus in the genomic era. Nat. Rev. Rheumatol. 6, 683–692 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Flesher, D.L., Sun, X., Behrens, T.W., Graham, R.R. & Criswell, L.A. Recent advances in the genetics of systemic lupus erythematosus. Expert Rev. Clin. Immunol. 6, 461–479 (2010).

    PubMed  PubMed Central  Google Scholar 

  9. Liu, K. et al. Kallikrein genes are associated with lupus and glomerular basement membrane-specific antibody-induced nephritis in mice and humans. J. Clin. Invest. 119, 911–923 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Sanchez, E. et al. Phenotypic associations of genetic susceptibility loci in systemic lupus erythematosus. Ann. Rheum. Dis. 70, 1752–1757 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Cantor, R.M., Lange, K. & Sinsheimer, J.S. Prioritizing GWAS results: a review of statistical methods and recommendations for their application. Am. J. Hum. Genet. 86, 6–22 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Zhang, J. et al. The autoimmune disease-associated PTPN22 variant promotes calpain-mediated Lyp/Pep degradation associated with lymphocyte and dendritic cell hyperresponsiveness. Nat. Genet. 43, 902–907 (2011).

    CAS  PubMed  Google Scholar 

  13. Rieck, M. et al. Genetic variation in PTPN22 corresponds to altered function of T and B lymphocytes. J. Immunol. 179, 4704–4710 (2007).

    CAS  PubMed  Google Scholar 

  14. Taylor, K.E. et al. Risk alleles for systemic lupus erythematosus in a large case-control collection and associations with clinical subphenotypes. PLoS Genet. 7, e1001311 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Askanase, A.D. et al. Use of pharmacogenetics, enzymatic phenotyping, and metabolite monitoring to guide treatment with azathioprine in patients with systemic lupus erythematosus. J. Rheumatol. 36, 89–95 (2009).

    CAS  PubMed  Google Scholar 

  16. Rubtsov, A.V., Rubtsova, K., Kappler, J.W. & Marrack, P. Genetic and hormonal factors in female-biased autoimmunity. Autoimmun. Rev. 9, 494–498 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Smith-Bouvier, D.L. et al. A role for sex chromosome complement in the female bias in autoimmune disease. J. Exp. Med. 205, 1099–1108 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Ravichandran, K.S. & Lorenz, U. Engulfment of apoptotic cells: signals for a good meal. Nat. Rev. Immunol. 7, 964–974 (2007).

    CAS  PubMed  Google Scholar 

  19. Marínez Valle, F., Balada, E., Ordi-Ros, J. & Vilardell-Tarres, M. DNase 1 and systemic lupus erythematosus. Autoimmun. Rev. 7, 359–363 (2008).

    Google Scholar 

  20. Rönnblom, L. & Alm, G.V. The natural interferon-α producing cells in systemic lupus erythematosus. Hum. Immunol. 63, 1181–1193 (2002).

    PubMed  Google Scholar 

  21. Blanco, P., Palucka, A.K., Gill, M., Pascual, V. & Banchereau, J. Induction of dendritic cell differentiation by IFN-α in systemic lupus erythematosus. Science 294, 1540–1543 (2001).

    CAS  PubMed  Google Scholar 

  22. Bennett, L. et al. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J. Exp. Med. 197, 711–723 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Bauer, J.W. et al. Elevated serum levels of interferon-regulated chemokines are biomarkers for active human systemic lupus erythematosus. PLoS Med. 3, e491 (2006).

    PubMed  PubMed Central  Google Scholar 

  24. Mathian, A., Weinberg, A., Gallegos, M., Banchereau, J. & Koutouzov, S. IFN-α induces early lethal lupus in preautoimmune (New Zealand Black × New Zealand White) F1 but not in BALB/c mice. J. Immunol. 174, 2499–2506 (2005).

    CAS  PubMed  Google Scholar 

  25. Ramanujam, M. et al. Interferon-α treatment of female (NZW × BXSB)F(1) mice mimics some but not all features associated with the Yaa mutation. Arthritis Rheum. 60, 1096–1101 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Nacionales, D.C. et al. Deficiency of the type I interferon receptor protects mice from experimental lupus. Arthritis Rheum. 56, 3770–3783 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Agrawal, H. et al. Deficiency of type I IFN receptor in lupus-prone New Zealand mixed 2328 mice decreases dendritic cell numbers and activation and protects from disease. J. Immunol. 183, 6021–6029 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Banchereau, J. & Pascual, V. Type I interferon in systemic lupus erythematosus and other autoimmune diseases. Immunity 25, 383–392 (2006).

    CAS  PubMed  Google Scholar 

  29. Thacker, S.G. et al. The detrimental effects of IFN-α on vasculogenesis in lupus are mediated by repression of IL-1 pathways: potential role in atherogenesis and renal vascular rarefaction. J. Immunol. 185, 4457–4469 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Garcia-Romo, G.S. et al. Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus. Sci. Transl. Med. 3, 73ra20 (2011).

    PubMed  PubMed Central  Google Scholar 

  31. Lande, R. et al. Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA-peptide complexes in systemic lupus erythematosus. Sci. Transl. Med. 3, 73ra19 (2011).

    PubMed  PubMed Central  Google Scholar 

  32. Charles, N., Hardwick, D., Daugas, E., Illei, G.G. & Rivera, J. Basophils and the T helper 2 environment can promote the development of lupus nephritis. Nat. Med. 16, 701–707 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Kawai, T. & Akira, S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34, 637–650 (2011).

    CAS  PubMed  Google Scholar 

  34. Boulé, M.W. et al. Toll-like receptor 9–dependent and –independent dendritic cell activation by chromatin-immunoglobulin G complexes. J. Exp. Med. 199, 1631–1640 (2004).

    PubMed  PubMed Central  Google Scholar 

  35. Lande, R. et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 449, 564–569 (2007).

    CAS  PubMed  Google Scholar 

  36. Tian, J. et al. Toll-like receptor 9–dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat. Immunol. 8, 487–496 (2007).

    CAS  PubMed  Google Scholar 

  37. Gilliet, M., Cao, W. & Liu, Y.J. Plasmacytoid dendritic cells: sensing nucleic acids in viral infection and autoimmune diseases. Nat. Rev. Immunol. 8, 594–606 (2008).

    CAS  PubMed  Google Scholar 

  38. Rönnblom, L. & Elkon, K.B. Cytokines as therapeutic targets in SLE. Nat. Rev. Rheumatol. 6, 339–347 (2010).

    PubMed  Google Scholar 

  39. Leadbetter, E.A. et al. Chromatin–IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416, 603–607 (2002).

    CAS  PubMed  Google Scholar 

  40. Berland, R. et al. Toll-like receptor 7–dependent loss of B cell tolerance in pathogenic autoantibody knockin mice. Immunity 25, 429–440 (2006).

    CAS  PubMed  Google Scholar 

  41. Christensen, S.R. & Shlomchik, M.J. Regulation of lupus-related autoantibody production and clinical disease by Toll-like receptors. Semin. Immunol. 19, 11–23 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Christensen, S.R. et al. Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. Immunity 25, 417–428 (2006).

    CAS  PubMed  Google Scholar 

  43. Fossati, L. et al. The Yaa gene-mediated acceleration of murine lupus: Yaa− T cells from non-autoimmune mice collaborate with Yaa+ B cells to produce lupus autoantibodies in vivo. Eur. J. Immunol. 25, 3412–3417 (1995).

    CAS  PubMed  Google Scholar 

  44. Barbalat, R., Ewald, S.E., Mouchess, M.L. & Barton, G.M. Nucleic acid recognition by the innate immune system. Annu. Rev. Immunol. 29, 185–214 (2011).

    CAS  PubMed  Google Scholar 

  45. Harley, J.B., Harley, I.T., Guthridge, J.M. & James, J.A. The curiously suspicious: a role for Epstein-Barr virus in lupus. Lupus 15, 768–777 (2006).

    CAS  PubMed  Google Scholar 

  46. Takaoka, A. et al. DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response. Nature 448, 501–505 (2007).

    CAS  PubMed  Google Scholar 

  47. Ishii, K.J. et al. TANK-binding kinase-1 delineates innate and adaptive immune responses to DNA vaccines. Nature 451, 725–729 (2008).

    CAS  PubMed  Google Scholar 

  48. Zhang, Z. et al. The helicase DDX41 senses intracellular DNA mediated by the adaptor STING in dendritic cells. Nat. Immunol. 12, 959–965 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Gall, A. et al. Autoimmunity initiates in nonhematopoietic cells and progresses via lymphocytes in an interferon-dependent autoimmune disease. Immunity 36, 120–131 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Goodnow, C.C., Vinuesa, C.G., Randall, K.L., Mackay, F. & Brink, R. Control systems and decision making for antibody production. Nat. Immunol. 11, 681–688 (2010).

    CAS  PubMed  Google Scholar 

  51. Arbuckle, M.R. et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N. Engl. J. Med. 349, 1526–1533 (2003).

    CAS  PubMed  Google Scholar 

  52. Moulton, V.R. & Tsokos, G.C. Abnormalities of T cell signaling in systemic lupus erythematosus. Arthritis Res. Ther. 13, 207 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Perl, A. et al. T-cell and B-cell signaling biomarkers and treatment targets in lupus. Curr. Opin. Rheumatol. 21, 454–464 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Crispín, J.C., Kyttaris, V.C., Terhorst, C. & Tsokos, G.C. T cells as therapeutic targets in SLE. Nat. Rev. Rheumatol. 6, 317–325 (2010).

    PubMed  PubMed Central  Google Scholar 

  55. Deng, G.M., Liu, L., Bahjat, F.R., Pine, P.R. & Tsokos, G.C. Suppression of skin and kidney disease by inhibition of spleen tyrosine kinase in lupus-prone mice. Arthritis Rheum. 62, 2086–2092 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Ichinose, K., Juang, Y.T., Crispin, J.C., Kis-Toth, K. & Tsokos, G.C. Suppression of autoimmunity and organ pathology in lupus-prone mice upon inhibition of calcium/calmodulin-dependent protein kinase type IV. Arthritis Rheum. 63, 523–529 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Bahjat, F.R. et al. An orally bioavailable spleen tyrosine kinase inhibitor delays disease progression and prolongs survival in murine lupus. Arthritis Rheum. 58, 1433–1444 (2008).

    CAS  PubMed  Google Scholar 

  58. Linterman, M.A. et al. Follicular helper T cells are required for systemic autoimmunity. J. Exp. Med. 206, 561–576 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Simpson, N. et al. Expansion of circulating T cells resembling follicular helper T cells is a fixed phenotype that identifies a subset of severe systemic lupus erythematosus. Arthritis Rheum. 62, 234–244 (2010).

    CAS  PubMed  Google Scholar 

  60. Odegard, J.M. et al. ICOS-dependent extrafollicular helper T cells elicit IgG production via IL-21 in systemic autoimmunity. J. Exp. Med. 205, 2873–2886 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Crispín, J.C. et al. Expanded double negative T cells in patients with systemic lupus erythematosus produce IL-17 and infiltrate the kidneys. J. Immunol. 181, 8761–8766 (2008).

    PubMed  PubMed Central  Google Scholar 

  62. Wardemann, H. & Nussenzweig, M.C. B-cell self-tolerance in humans. Adv. Immunol. 95, 83–110 (2007).

    CAS  PubMed  Google Scholar 

  63. Liu, Z. & Davidson, A. BAFF and selection of autoreactive B cells. Trends Immunol. 32, 388–394 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Arechiga, A.F. et al. Cutting edge: the PTPN22 allelic variant associated with autoimmunity impairs B cell signaling. J. Immunol. 182, 3343–3347 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Menard, L. et al. The PTPN22 allele encoding an R620W variant interferes with the removal of developing autoreactive B cells in humans. J. Clin. Invest. 121, 3635–3644 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Cappione, A. III et al. Germinal center exclusion of autoreactive B cells is defective in human systemic lupus erythematosus. J. Clin. Invest. 115, 3205–3216 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Gonzalez, S.F. et al. Trafficking of B cell antigen in lymph nodes. Annu. Rev. Immunol. 29, 215–233 (2011).

    CAS  PubMed  Google Scholar 

  68. Kranich, J. et al. Follicular dendritic cells control engulfment of apoptotic bodies by secreting Mfge8. J. Exp. Med. 205, 1293–1302 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Blair, P.A. et al. CD19+CD24hiCD38hi B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic lupus erythematosus patients. Immunity 32, 129–140 (2010).

    CAS  PubMed  Google Scholar 

  70. Campbell, D.J. & Koch, M.A. Treg cells: patrolling a dangerous neighborhood. Nat. Med. 17, 929–930 (2011).

    CAS  PubMed  Google Scholar 

  71. Kim, H.J. et al. CD8+ T regulatory cells express the Ly49 Class I MHC receptor and are defective in autoimmune prone B6-Yaa mice. Proc. Natl. Acad. Sci. USA 108, 2010–2015 (2011).

    CAS  PubMed  Google Scholar 

  72. Brownlie, R.J. et al. Distinct cell-specific control of autoimmunity and infection by FcgammaRIIb. J. Exp. Med. 205, 883–895 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Kim, S.J. et al. Increased IL-12 inhibits B cell differentiation to germinal center plasma cells and promotes differentiation to short-lived plasmablasts. J. Exp. Med. 205, 2437–2448 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Herlands, R.A., William, J., Hershberg, U. & Shlomchik, M.J. Anti-chromatin antibodies drive in vivo antigen-specific activation and somatic hypermutation of rheumatoid factor B cells at extrafollicular sites. Eur. J. Immunol. 37, 3339–3351 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Erickson, L.D. et al. Short-circuiting long-lived humoral immunity by the heightened engagement of CD40. J. Clin. Invest. 109, 613–620 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Cassese, G. et al. Inflamed kidneys of NZB/W mice are a major site for the homeostasis of plasma cells. Eur. J. Immunol. 31, 2726–2732 (2001).

    CAS  PubMed  Google Scholar 

  77. Tokoyoda, K., Hauser, A.E., Nakayama, T. & Radbruch, A. Organization of immunological memory by bone marrow stroma. Nat. Rev. Immunol. 10, 193–200 (2010).

    CAS  PubMed  Google Scholar 

  78. Merrill, J.T. et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum. 62, 222–233 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Benson, M.J. et al. Cutting edge: the dependence of plasma cells and independence of memory B cells on BAFF and APRIL. J. Immunol. 180, 3655–3659 (2008).

    CAS  PubMed  Google Scholar 

  80. Jacobi, A.M. et al. Effect of long-term belimumab treatment on B cells in systemic lupus erythematosus: extension of a phase II, double-blind, placebo-controlled, dose-ranging study. Arthritis Rheum. 62, 201–210 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Looney, R.J., Anolik, J. & Sanz, I. A perspective on B-cell–targeting therapy for SLE. Mod. Rheumatol. 20, 1–10 (2010).

    PubMed  Google Scholar 

  82. Aringer, M. et al. Current state of evidence on “off label” therapeutic options for systemic lupus erythematosus, including biological immunosuppressive agents, in Germany, Austria, and Switzerland—a consensus report. Lupus 21, 386–401 (2012).

    CAS  PubMed  Google Scholar 

  83. Hahn, B.H. Targeted therapies in systemic lupus erythematosus: successes, failures and future. Ann. Rheum. Dis. 70 (suppl. 1), i64–i66 (2011).

    CAS  PubMed  Google Scholar 

  84. de Laat, B., Mertens, K. & de Groot, P.G. Mechanisms of disease: antiphospholipid antibodies—from clinical association to pathologic mechanism. Nat. Clin. Pract. Rheumatol. 4, 192–199 (2008).

    CAS  PubMed  Google Scholar 

  85. Lauvsnes, M.B. & Omdal, R. Systemic lupus erythematosus, the brain, and anti-NR2 antibodies. J. Neurol. 259, 622–629 (2012).

    CAS  PubMed  Google Scholar 

  86. Faust, T.W. et al. Neurotoxic lupus autoantibodies alter brain function through two distinct mechanisms. Proc. Natl. Acad. Sci. USA 107, 18569–18574 (2010).

    CAS  PubMed  Google Scholar 

  87. DeGiorgio, L.A. et al. A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus. Nat. Med. 7, 1189–1193 (2001).

    CAS  PubMed  Google Scholar 

  88. Matus, S. et al. Antiribosomal-P autoantibodies from psychiatric lupus target a novel neuronal surface protein causing calcium influx and apoptosis. J. Exp. Med. 204, 3221–3234 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Kowal, C. et al. Cognition and immunity; antibody impairs memory. Immunity 21, 179–188 (2004).

    CAS  PubMed  Google Scholar 

  90. Turnberg, D. & Cook, H.T. Complement and glomerulonephritis: new insights. Curr. Opin. Nephrol. Hypertens. 14, 223–228 (2005).

    CAS  PubMed  Google Scholar 

  91. Bergtold, A., Gavhane, A., D'Agati, V., Madaio, M. & Clynes, R. FcR-bearing myeloid cells are responsible for triggering murine lupus nephritis. J. Immunol. 177, 7287–7295 (2006).

    CAS  PubMed  Google Scholar 

  92. Anders, H.J. & Schlondorff, D. Toll-like receptors: emerging concepts in kidney disease. Curr. Opin. Nephrol. Hypertens. 16, 177–183 (2007).

    CAS  PubMed  Google Scholar 

  93. Manderson, A.P., Botto, M. & Walport, M.J. The role of complement in the development of systemic lupus erythematosus. Annu. Rev. Immunol. 22, 431–456 (2004).

    CAS  PubMed  Google Scholar 

  94. Woodruff, T.M., Nandakumar, K.S. & Tedesco, F. Inhibiting the C5-C5a receptor axis. Mol. Immunol. 48, 1631–1642 (2011).

    CAS  PubMed  Google Scholar 

  95. Vielhauer, V., Anders, H.J. & Schlondorff, D. Chemokines and chemokine receptors as therapeutic targets in lupus nephritis. Semin. Nephrol. 27, 81–97 (2007).

    CAS  PubMed  Google Scholar 

  96. Kitching, A.R. & Holdsworth, S.R. The emergence of TH17 cells as effectors of renal injury. J. Am. Soc. Nephrol. 22, 235–238 (2011).

    CAS  PubMed  Google Scholar 

  97. Ernandez, T. & Mayadas, T.N. Immunoregulatory role of TNFα in inflammatory kidney diseases. Kidney Int. 76, 262–276 (2009).

    CAS  PubMed  Google Scholar 

  98. Bethunaickan, R. et al. A unique hybrid renal mononuclear phagocyte activation phenotype in murine systemic lupus erythematosus nephritis. J. Immunol. 186, 4994–5003 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Hill, G.S. et al. Predictive power of the second renal biopsy in lupus nephritis: significance of macrophages. Kidney Int. 59, 304–316 (2001).

    CAS  PubMed  Google Scholar 

  100. Schlondorff, D.O. Overview of factors contributing to the pathophysiology of progressive renal disease. Kidney Int. 74, 860–866 (2008).

    CAS  PubMed  Google Scholar 

  101. Deelman, L. & Sharma, K. Mechanisms of kidney fibrosis and the role of antifibrotic therapies. Curr. Opin. Nephrol. Hypertens. 18, 85–90 (2009).

    CAS  PubMed  Google Scholar 

  102. Alarcón, G.S. et al. Time to renal disease and end-stage renal disease in PROFILE: a multiethnic lupus cohort. PLoS Med. 3, e396 (2006).

    PubMed  PubMed Central  Google Scholar 

  103. Esdaile, J.M. et al. Traditional Framingham risk factors fail to fully account for accelerated atherosclerosis in systemic lupus erythematosus. Arthritis Rheum. 44, 2331–2337 (2001).

    CAS  PubMed  Google Scholar 

  104. Symmons, D.P. & Gabriel, S.E. Epidemiology of CVD in rheumatic disease, with a focus on RA and SLE. Nat. Rev. Rheumatol. 7, 399–408 (2011).

    PubMed  Google Scholar 

  105. Narshi, C.B., Giles, I.P. & Rahman, A. The endothelium: an interface between autoimmunity and atherosclerosis in systemic lupus erythematosus? Lupus 20, 5–13 (2011).

    CAS  PubMed  Google Scholar 

  106. Lopez, L.R. et al. Oxidized low-density lipoprotein and β2-glycoprotein I in patients with systemic lupus erythematosus and increased carotid intima-media thickness: implications in autoimmune-mediated atherosclerosis. Lupus 15, 80–86 (2006).

    CAS  PubMed  Google Scholar 

  107. Matsuura, E., Kobayashi, K., Hurley, B.L. & Lopez, L.R. Atherogenic oxidized low-density lipoprotein/β2-glycoprotein I (oxLDL/β2GPI) complexes in patients with systemic lupus erythematosus and antiphospholipid syndrome. Lupus 15, 478–483 (2006).

    CAS  PubMed  Google Scholar 

  108. Skaggs, B.J., Hahn, B.H., Sahakian, L., Grossman, J. & McMahon, M. Dysfunctional, pro-inflammatory HDL directly upregulates monocyte PDGFRβ, chemotaxis and TNFα production. Clin. Immunol. 137, 147–156 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. McMahon, M. et al. Dysfunctional proinflammatory high-density lipoproteins confer increased risk of atherosclerosis in women with systemic lupus erythematosus. Arthritis Rheum. 60, 2428–2437 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Schanberg, L.E. et al. Use of atorvastatin in systemic lupus erythematosus in children and adolescents. Arthritis Rheum. 64, 285–296 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Petri, M.A., Kiani, A.N., Post, W., Christopher-Stine, L. & Magder, L.S. Lupus Atherosclerosis Prevention Study (LAPS). Ann. Rheum. Dis. 70, 760–765 (2011).

    CAS  PubMed  Google Scholar 

  112. Ceribelli, A., Yao, B., Dominguez-Gutierrez, P.R. & Chan, E.K. Lupus T cells switched on by DNA hypomethylation via microRNA? Arthritis Rheum. 63, 1177–1181 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Pan, Y. & Sawalha, A.H. Epigenetic regulation and the pathogenesis of systemic lupus erythematosus. Transl. Res. 153, 4–10 (2009).

    CAS  PubMed  Google Scholar 

  114. Dai, R. & Ahmed, S.A. MicroRNA, a new paradigm for understanding immunoregulation, inflammation, and autoimmune diseases. Transl. Res. 157, 163–179 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Ceribelli, A. et al. MicroRNAs in systemic rheumatic diseases. Arthritis Res. Ther. 13, 229 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Geuking, M.B. et al. Intestinal bacterial colonization induces mutualistic regulatory T cell responses. Immunity 34, 794–806 (2011).

    CAS  PubMed  Google Scholar 

  117. Illei, G.G. et al. Current state and future directions of autologous hematopoietic stem cell transplantation in systemic lupus erythematosus. Ann. Rheum. Dis. 70, 2071–2074 (2011).

    PubMed  PubMed Central  Google Scholar 

  118. Choi, E.W. et al. Reversal of serological, immunological and histological dysfunction in systemic lupus erythematosus mice by long-term serial adipose tissue-derived mesenchymal stem cell transplantation. Arthritis Rheum. 64, 243–253 (2012).

    CAS  PubMed  Google Scholar 

  119. Liang, J. et al. Allogenic mesenchymal stem cells transplantation in refractory systemic lupus erythematosus: a pilot clinical study. Ann. Rheum. Dis. 69, 1423–1429 (2010).

    PubMed  Google Scholar 

  120. Mok, C.C. Biomarkers for lupus nephritis: a critical appraisal. J. Biomed. Biotechnol. 2010, 638413 (2010).

    PubMed  PubMed Central  Google Scholar 

  121. Bauer, J.W. et al. Interferon-regulated chemokines as biomarkers of systemic lupus erythematosus disease activity: a validation study. Arthritis Rheum. 60, 3098–3107 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Chaussabel, D. et al. A modular analysis framework for blood genomics studies: application to systemic lupus erythematosus. Immunity 29, 150–164 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Hinze, C.H. et al. Neutrophil gelatinase-associated lipocalin is a predictor of the course of global and renal childhood-onset systemic lupus erythematosus disease activity. Arthritis Rheum. 60, 2772–2781 (2009).

    PubMed  PubMed Central  Google Scholar 

  124. Rovin, B.H. et al. Urine chemokines as biomarkers of human systemic lupus erythematosus activity. J. Am. Soc. Nephrol. 16, 467–473 (2005).

    CAS  PubMed  Google Scholar 

  125. Rubinstein, T. et al. Urinary neutrophil gelatinase-associated lipocalin as a novel biomarker for disease activity in lupus nephritis. Rheumatology (Oxford) 49, 960–971 (2010).

    CAS  Google Scholar 

  126. Guiducci, C. et al. TLR recognition of self nucleic acids hampers glucocorticoid activity in lupus. Nature 465, 937–941 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Yuan, W., DiMartino, S.J., Redecha, P.B., Ivashkiv, L.B. & Salmon, J.E. Systemic lupus erythematosus monocytes are less responsive to interleukin-10 in the presence of immune complexes. Arthritis Rheum. 63, 212–218 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Ramanujam, M. & Davidson, A. Targeting of the immune system in systemic lupus erythematosus. Expert Rev. Mol. Med. 10, e2 (2008).

    PubMed  Google Scholar 

  129. Wofsy, D.S., Shropshire, S.M., Hillson, J.L. & Diamond, B. Abatacept for lupus nephritis: alternative outcome measures support opposing interpretations of data From a multicenter, randomized, double-blind, placebo-controlled phase II/III study. ACR presentation, number 2474 (8 November 2011).

  130. Lenert, P.S. Classification, mechanisms of action, and therapeutic applications of inhibitory oligonucleotides for Toll-like receptors (TLR) 7 and 9. Mediators Inflamm. 2010, 986596 (2010).

    PubMed  PubMed Central  Google Scholar 

  131. Kyttaris, V.C. & Tsokos, G.C. Targeting lymphocyte signaling pathways as a therapeutic approach to systemic lupus erythematosus. Curr. Opin. Rheumatol. 23, 449–453 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Schiffer, L. et al. Short term administration of costimulatory blockade and cyclophosphamide induces remission of systemic lupus erythematosus nephritis in NZB/W F1 mice by a mechanism downstream of renal immune complex deposition. J. Immunol. 171, 489–497 (2003).

    CAS  PubMed  Google Scholar 

  133. Daikh, D.I. & Wofsy, D. Cutting edge: reversal of murine lupus nephritis with CTLA4Ig and cyclophosphamide. J. Immunol. 166, 2913–2916 (2001).

    CAS  PubMed  Google Scholar 

  134. Ng, K.P. et al. B cell depletion therapy in systemic lupus erythematosus: long-term follow-up and predictors of response. Ann. Rheum. Dis. 66, 1259–1262 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Bloom, O. et al. Generation of a unique small molecule peptidomimetic that neutralizes lupus autoantibody activity. Proc. Natl. Acad. Sci. USA 108, 10255–10259 (2011).

    CAS  PubMed  Google Scholar 

  136. Clynes, R., Dumitru, C. & Ravetch, J.V. Uncoupling of immune complex formation and kidney damage in autoimmune glomerulonephritis. Science 279, 1052–1054 (1998).

    CAS  PubMed  Google Scholar 

  137. Gambaro, G. & Kong, N.C. Glycosaminoglycan treatment in glomerulonephritis? An interesting option to investigate. J. Nephrol. 23, 244–252 (2010).

    PubMed  Google Scholar 

  138. Nguyen, T.Q. & Goldschmeding, R. Bone morphogenetic protein-7 and connective tissue growth factor: novel targets for treatment of renal fibrosis? Pharm. Res. 25, 2416–2426 (2008).

    CAS  PubMed  Google Scholar 

  139. Renner, B. et al. Binding of factor H to tubular epithelial cells limits interstitial complement activation in ischemic injury. Kidney Int. 80, 165–173 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Tse, K.C. et al. Angiotensin inhibition or blockade for the treatment of patients with quiescent lupus nephritis and persistent proteinuria. Lupus 14, 947–952 (2005).

    CAS  PubMed  Google Scholar 

  141. McMahon, M., Hahn, B.H. & Skaggs, B.J. Systemic lupus erythematosus and cardiovascular disease: prediction and potential for therapeutic intervention. Expert Rev. Clin. Immunol. 7, 227–241 (2011).

    PubMed  PubMed Central  Google Scholar 

  142. Stohl, W. et al. Belimumab reduces autoantibodies, normalizes low complement, and reduces select B-cell populations in patients with systemic lupus erythematosus. Arthritis Rheum. published online doi:10.1002/art.34400 (24 January 2012).

  143. Liu, Z. & Davidson, A. BAFF inhibition: a new class of drugs for the treatment of autoimmunity. Exp. Cell Res. 317, 1270–1277 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Mackay, F. & Schneider, P. Cracking the BAFF code. Nat. Rev. Immunol. 9, 491–502 (2009).

    CAS  PubMed  Google Scholar 

  145. Stohl, W. et al. Belimumab reduces autoantibodies, normalizes low complement, and reduces select B-cell populations in patients with systemic lupus erythematosus. Arthritis Rheum. published online doi:10.1002/art.34400 (24 January 2012).

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Acknowledgements

This work was supported by US National Institutes of Health grants R01 DK085241-01, R01 AI083901 and R21 AR057930. The authors thank T. Rothstein and A. Boneparth for critical reading of the manuscript.

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  1. Center for Autoimmunity and Musculoskeletal Diseases, Feinstein Institute for Medical Research, Manhasset, New York, USA

    Zheng Liu & Anne Davidson

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Correspondence to Anne Davidson.

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Liu, Z., Davidson, A. Taming lupus—a new understanding of pathogenesis is leading to clinical advances. Nat Med 18, 871–882 (2012). https://doi.org/10.1038/nm.2752

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